CN108289963B

CN108289963B - Methods and products for testing response to oral glucose load

Info

Publication number: CN108289963B
Application number: CN201680069899.XA
Authority: CN
Inventors: I·巴拉巴什; N·吉沃尼; F·梅瑟; T·P·克拉尔杰
Original assignee: Inr Enterprises Pty Ltd
Current assignee: Inr Enterprises Pty Ltd
Priority date: 2015-11-06
Filing date: 2016-11-05
Publication date: 2023-08-29
Anticipated expiration: 2036-11-05
Also published as: CN116459354A; CN108289963A; EP3370776A1; EP3370776B1; CA3003915A1; EP3370776A4; WO2017075672A1; AU2016351301A1; US10983132B2; AU2016351301B2; US20180321249A1; DK3370776T3

Abstract

In a first aspect, the present invention provides a method of performing an oral glucose tolerance or challenge test on a patient, the method comprising the steps of: (i) Administering to the patient a prescribed amount of a drinkable gel formulation (1) containing glucose as the main saccharide; (ii) Measuring the plasma glucose concentration of the patient at one or more prescribed time points for the administering step; and (iii) determining the glucose tolerance of the patient based on the plasma glucose concentration at the specified time point. In another aspect, the invention provides a glucose dosage form (1) formulated in a drinkable gel, which provides an amount suitable for performing an oral glucose tolerance or challenge test on a patient.

Description

Methods and products for testing response to oral glucose load

Technical Field

The present invention relates to human tests designed to determine the intake response to oral glucose load, such as the Oral Glucose Tolerance Test (OGTT) and the oral glucose challenge test (glucose challenge test) (OGCT).

Background

An Oral Glucose Tolerance Test (OGTT) has been used for many years to determine how fast glucose is cleared from the blood. The assay may be used to detect diabetes, insulin resistance or other conditions of glucose metabolism.

The general procedure for OGTT is to collect a blood sample from an overnight fast patient at zero time and then drink a measured dose of glucose solution to the patient within a short period of time (typically 5 minutes). When practiced in the united states, generally, all adults are dosed at 75g glucose, or alternatively, 1.75g glucose per kilogram of body weight to a maximum of 75g.

Blood sample measurements were then taken at different time intervals after dosing. For simple diabetes screening, the most important sample is two hours after dosing, and in a simple form of the test, only the glucose concentrations of the 0 and 2 hour samples can be collected and analyzed.

Blood glucose (measured before the start of OGTT) should be below 6.1mmol/L (110 mg/dL) at zero time. Fasting levels between 6.1 and 7.0mmol/L (110 and 125 mg/dL) are borderline ("impaired fasting glucose") and fasting levels at or above 7.0mmol/L (126 mg/dL) are diagnosed as diabetic. OGTT glucose levels below 7.8mmol/L (140 mg/dL) were normal for 2 hours, while higher glucose levels indicated hyperglycemia. Plasma glucose between 7.8mmol/L (140 mg/dL) and 11.1mmol/L (200 mg/dL) indicates "impaired glucose tolerance", and plasma glucose levels above 11.1mmol/L (200 mg/dL) at 2 hours confirm diagnosis of diabetes.

The Oral Glucose Challenge Test (OGCT) is a simpler form of OGTT that is used to examine the signs of gestational diabetes in pregnant women. It was performed in a non-fasting state, including ingestion of 50g of glucose instead of 75g, and reading after 1 hour.

Many patients find oral glucose drinks containing 50g or 75g glucose highly unpleasant and many suffer from nausea, abdominal distension, gastrointestinal pain or vomiting.

Some hospitals recommend patients to take a large number of fudge (jellybeans) instead, as they believe that the sugars (carbohydrates) provided by the various sugars in the fudge may be equivalent to the oral glucose fluid load, although the specific number and brand of fudge that may be equivalent has not been determined. Bean-shaped fondants generally contain 53% sucrose, 14% dextrose (glucose), 6% cornstarch, and 18% higher sugars (saccharoses). In 2010, kevin F.Foley, phD and Shirley L.Welch, phD published in CAP Today concluded that those using the "off-label" method appeared to use inconsistent amounts or brands of bean-shaped soft candy. As required by CLIA, the pre-analysis test thing is under the authority (purview) of the laboratory principal and manager. It is believed that the advantages of applying marshmallow in the parturient to be expected without the risk of strong false negative screening. Until the method is confirmed, the bean-shaped soft candy should stay in the Easter basket (Easter baskett) and go out of the clinic. "

The fact that nonstandard and uncontrollable methods like bean-shaped fondants become common is demonstrated by the practical problem of sensory challenges faced by professionals using OGTT when faced with many patients who find intake of liquid glucose difficult. Accordingly, there is a need to provide an improved product and method for administering standardized glucose loads.

The present inventors have conceived an improved method and product that can maintain the accuracy of the liquid glucose method while avoiding the drawbacks thereof.

Brief description of the invention

The present inventors have recognized that the primary cause of unpleasant and nausea in current glucose formulations is the intense sweetness of the formulation upon ingestion, which can be improved without resorting to solid dosage forms.

Thus, according to one broad aspect of the present invention, there is provided a method of performing an oral glucose tolerance or challenge test on a patient, the method comprising the steps of:

(i) Administering to the patient a prescribed amount of a drinkable gel formulation containing glucose as the primary saccharide;

(ii) Measuring the plasma glucose concentration of the patient at one or more prescribed time points for the administering step; and

(iii) The glucose tolerance of the patient is determined from the plasma glucose concentration at the prescribed time point.

In one embodiment, the determining step comprises using a normalization function that has been calibrated by a control clinical trial that compares the plasma glucose concentration of a patient administered a standardized liquid glucose formulation to the plasma glucose concentration of a patient administered a drinkable gel formulation or equivalent thereof. The control clinical trial may compare the plasma glucose concentration two hours after administration of the one or more doses of glucose of the standard liquid glucose formulation to the plasma glucose concentration two hours after administration of the one or more doses of glucose provided in the drinkable gel formulation or equivalent thereof.

In one embodiment, the drinkable gel formulation contains substantially pure glucose as the saccharide.

In one embodiment, the drinkable gel formulation comprises an effective amount of a gelling agent such that the Bloom grade is at least 100g, preferably at least 140g, further preferably at least 160g, even further preferably at least 180g, and most preferably at least 200g.

In one embodiment, the gelling agent comprises agar.

In one embodiment, the gelling agent comprises agar and locust bean gum.

In one embodiment, the drinkable gel formulation comprises an aqueous dextrose solution with a gelling agent.

In one embodiment, the drinkable gel formulation comprises glucose in an amount suitable for oral glucose challenge test and is provided in a plastic pouch.

According to a second broad aspect of the present invention, there is provided a glucose dosage form formulated in a drinkable gel which provides glucose in an amount suitable for an oral glucose tolerance or challenge test on a patient.

In one embodiment, the dosage form is contained in a plastic bag.

In one embodiment, the amount is 50 grams or 75 grams of glucose.

In one embodiment, the drinkable gel formulation comprises an effective amount of a gelling agent such that said drinkable gel formulation has a bloom rating of at least 100g, more preferably 140g, 160g, 180g, and most preferably at least 200g.

In one embodiment, the drinkable gel formulation comprises a gelling agent consisting essentially of agar.

In one embodiment, the drinkable gel formulation comprises agar as the primary gelling agent, locust bean gum as the secondary gelling agent, and the pH of the drinkable gel formulation is adjusted considering a balance of ease of consumption and palatability.

In one embodiment, the drinkable gel formulation has a pH of less than 6.0 and greater than 4.0.

Detailed description of the embodiments

Embodiments of the present invention will now be described.

Preparation of gel formulations

This embodiment relates to a glucose tolerance test and aims to produce a dose of glucose equivalent to a standard glucose solution of 75g glucose dissolved in 150ml of water with a rapid blood glucose uptake similar to that of the self-intestinal tract, but in a modified gel formulation it reduces sensory challenges by providing a sufficient degree of sweetness reduction, essentially partially masking to minimize the taste that would otherwise significantly reduce compliance.

From a range of prototype simplifications (prototype compacts), granules, gels and frozen forms, gels friendly to islets (halal), kosher (kosher) and vegetarian (vegan) are considered the best candidates.

The formulation compositions are provided in table 1 below.

The experiment uses 0.1M HCl to adjust the pH of the solution to about 5.6 or 4.3 for comparison purposes.

The preparation method of the gel comprises the following steps: the water was stirred to dissolve glucose, preservative and HCl in the water. For the addition of the gelling agent, the solution must be stirred and heated until boiling, and the gelling agent must be gradually added to achieve satisfactory dispersion and kept boiling for 4-5 minutes. This is required to ensure proper hydration of the agar, and to form a hard gel. However, the shortest suitable heating is advantageous because it reduces the loss of evaporated moisture-which can lead to product variability. After heating, the solution may be hot poured into a desired container (such as pouch 1 as described below) and allowed to cool, then gel.

Gel strength varies with the method of preparation, water content, nature and concentration of the gelling agent, and pH. The gel may also be sheared to render it more fluid. However, softer drinkable gels, such as those produced in this case, allow for more exudation/leakage of free, non-gelled glucose solutions. This results in a product that is sweeter than a hard gel, and therefore the present invention best achieves a compromise between softness to provide drinkability and hardness to minimize unpleasant sweetness.

Gel strength can be quantified by measuring the boruhm scale, as is known in the art. The bloom rating is defined as the amount of force required to press the probe into the gelatin gel surface by 4 mm. Standard tests involved preparing a 6.67% w/w gelatin gel, heating and mixing, standing to room temperature and adjusting to 10 degrees for 16 hours. In this example, the cylindrical probe was taped to a load cell that was held by a holder so that it could move a beaker containing the test gel toward the probe. The deformation (Deflection) of the gel of 4mm was measured using a ruler. Standard solutions of three gelatin gels were prepared to measure the baseline bloom rating of the device. These 3 standards gave a bloom rating of 156g, which is slightly below the 180g bloom rating that it was expected to publish as a standard.

Both formulations gave final raw deformation values of 199g at pH 5.6 and 181g at pH 4.3. The true bloom rating of the formulation may be slightly higher than the original measurement, taking into account the difference between the standard and published 180g bloom rating. A bloom rating of greater than 100g is expected to preferably result in a reduced sweetness gel. More preferably, the boruhm grade should be greater than 140g, further preferably greater than 160g, further preferably greater than 180g, and most preferably greater than 200g. Such adjustment may be obtained by varying the concentration and pH of the gelling agent.

Formulations with pH 4.3 were found to be preferred in taste tests, palatable and readily consumable. Formulations at pH 5.6 are equally palatable but harder and more difficult to consume. Thinner formulations obtained by lowering the pH below 4.3 were observed to give lower hardness and significantly sweeter and less palatable formulations.

The potassium sorbate used in the sample (protype) examples above was used as evidence for the concept: preservatives of slightly acidic pH may be included without significant impact on gel properties. However, potassium sorbate may be insufficiently active as a preservative at pH 5.6, and alternative preservatives may be suitable at pH 5.6.

Based on the observation of short-term storage of the above prototypes, the gel formulation appeared to be physically stable, provided that the container remained sealed to prevent dehydration.

Dispensing dosage forms

Referring now to fig. 1, a single dose dispensing dosage form suitable for a single patient comprises a plastic pouch 1 containing a standardised amount of gel formulation 2, typically 50g or 75g. Pouch 1 is formed from a plastic layer that seals together with rim 3 for the introduction of the filling and a dispensing orifice (dispensing aperture) comprising a plug 4, a spout (spout) 5 and a cap 6. The pouch 1 is filled with the formulation via a mouthpiece (mouthpiece) 5 and fastened with a lid 6, the lid 6 may have a frangible seal. The pouches 1 can be pre-filled in the production facility to ensure accurate dispensing.

Usage method

In use, the patient removes the cap 6 and drinks the gel formulation 2 while sucking the gel formulation 2 by sucking on the mouthpiece 5 or squeezing the pouch 1 or a combination thereof, thereby sucking and drinking substantially all of the contents of the pouch 1 in a reasonably feasible short time as in a standard test to establish a well-defined dosing time point. Glucose tolerance or challenge tests are normally performed and plasma glucose concentrations are measured at one or more defined time points after the administration time.

Calibration of

Control experiments that can be performed to determine the normalization function can have many designs. Experiments on patient groups should compare blood glucose measurements at a defined time point after administration of the drinkable gel formulation with blood glucose measurements at a defined time point after administration of the standard glucose drink. Desirably, but not necessarily, the dosages of the two different formulations are the same, and the time points at which the measurements are made are the same. It is also desirable, but not necessary, that each dose in different situations be compared using the same patient, and that this crossover design may be appropriate. It is also desirable, but not necessary, to administer more than one dose of each formulation.

Based on the generated clinical data, the calibration may then correlate blood glucose of the drinkable gel formulation with corresponding blood glucose according to a conventional liquid glucose drink formulation regimen. Of course, as will be appreciated by those skilled in the art of clinical trial design, there are many different ways to achieve the calibration objective of providing a function of patient glucose tolerance as determined by plasma glucose concentration at a prescribed point in time using a drinkable gel formulation. Ideally, the clinical data confirm that the same function as known in the prior art for liquid formulations is suitable for drinkable gel formulations, and therefore that the same value of blood glucose value corresponds to the same interpretation as for the case of blood glucose tolerance as used for liquid formulations. In fact, a significant difference between the two formulations is observed, in which case a calibration function can be determined for converting the blood glucose measurement under the new formulation into an equivalent blood glucose measurement under the liquid glucose drink formulation.

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Those skilled in the art will appreciate that many changes can be made to the invention without departing from the scope thereof.

For example, in one broadest aspect of the invention, the above-described calibration clinical trial is not required, and the calibration clinical trial may be performed by another set of drinkable gel formulations or equivalent drinkable gel formulations, as defined in one or more of the claims herein.

Further, it will be appreciated by those skilled in the art that the adjustment of the gel properties may be made in various ways, such as changing the nature and proportion of the gelling agent, the concentration of the formulation and the pH. Such variations are within the broadest scope of the invention extending to any drinkable gel formulation.

In the following claims and in the foregoing description of the invention, unless context requires otherwise due to the express term or necessary implication, the term "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. Further, any method steps recited in the claims do not necessarily imply that they are performed in the order in which they are written, or that they do not necessarily stop once they are started, unless the context requires.

It will be appreciated that in australia or any other country, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art.

Claims

1. A glucose dosage form that is a drinkable gel comprising glucose comprising:

a. water;

b. agar as the primary gelling agent, locust bean gum as the secondary gelling agent; and

a pH regulator;

which is present in an amount to ensure proper hydration and formation of a hard gel having a bloom rating of above 180 which can be sheared to render it more fluid so that it is a drinkable gel, wherein the pH of the drinkable gel is adjusted to a pH of 4.3 to pH 5.6.

2. The dosage form of claim 1, further comprising

d. And (3) a preservative.

3. A dosage form according to claim 1, packaged in a pouch (1) having a mouth (5) such that all contents of the pouch can be sucked and drunk by sucking on the mouth (5) or squeezing the pouch (1) or a combination thereof to suck the drinkable gel.

4. A dosage form as claimed in any one of claims 1 to 3, comprising 50g or 75g glucose.

5. A dosage form as claimed in any one of claims 1 to 3, comprising 100ml or 150ml of water.

6. Use of a glucose dosage form according to any one of claims 1 to 5 for the manufacture of a medicament for oral glucose tolerance or challenge testing of a patient.